There have been great efforts devoted to improving methods for safely transporting drugs across the blood brain barrier (BBB). Recently, a large amount of research has been directed to the application of electric or magnetic fields to facilitate the transport of drugs across the BBB.
Martel et al. in US 2015/0126964 state that magnetically heatable entities (MHEs) can be piloted from an injection point to a location of the BBB and then using an alternating magnetic field to heat the MHEs. Advantageously the MHEs are superparamagnetic. Application of an AC field heats the MHEs leading to transient disruption of the BBB, thus facilitating delivery of therapeutic agents. A scientific paper by several of the inventors of the Martel patent application is Tabatabaei S J, Girouard H, Carret A-S, Martel S., entitled “Remote control of the permeability of the blood-brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery”, Journal of Controlled Release, 206 (2015) page 49-57. The authors reported that “we show that the thermal energy generated by magnetic heating (hyperthermia) of commercially available magnetic nanoparticles (MNPs) in the brain capillaries of rats can transiently increase barrier permeability . . . . Results indicate a substantial but reversible opening of the BBB where hyperthermia is applied.” In this paper, the authors stated that “when MNPs are deposited, they remain on the surface of the target endothelium for the duration of our technique.”
Several patents have discussed nanoparticles and the BBB. International patent application no. WO201474584 describes a method comprising administering to a subject a plurality of magneto-electric nanoparticles (MENP) having a drug associated thereto through an ionic bond; and applying a magnetic field to the subject to weaken the ionic bond thereby releasing at least a portion of the drug from the MENP. The MENP may be CoFe2O4@BaTiO3. Khizroev et al. in US 20130317279 describe a method of using magneto-electro nanoparticles that pass through the BBB into the brain where they are actuated by an external AC magnetic field. Jin et al. in U.S. Pat. No. 8,968,699 describe hollow nanospheres comprising a drug (such as an anti-nerve agent) and further comprising magnetically actuable superparamagnetic nanoparticles and a polymer coating. A magnetic field can be used to activate the nanospheres and release drug inside the brain. The nanoparticles can be heated to disrupt the BBB for easier crossing.
WO2014125256 describes a method of delivering at least one agent to the central nervous system (CNS). The composition comprises: (a) a nanoparticle comprising: (i) a magnetic core; (ii) a corona comprising a plurality of ligands covalently linked to the core, wherein said ligands comprise a carbohydrate, insulin and/or a glutathione; and (b) at least one agent to be delivered to the CNS.
Gordon in U.S. Pat. No. 4,813,399 states that ferromagnetic particles that are under 1 μm in size can be injected into a patient. A steady magnetic or electric field may be used to enhance uptake of the particles by neuronal cells. Example IV describes a colloidal solution of Fe3O4-dextran-transferrin injected into a myelinated nerve.
Friedman et al. in WO 2015/038924 describes coating paramagnetic nanoparticles with a lipophilic drug and a polymer. The drug-bearing nanoparticles cross the BBB with the aid of a magnetic field. Although not described in detail, Friedman et al. suggest that the drug-bearing nanoparticles can be combined with chemotherapeutic agents.
Pell et al. in WO2013121359 describes a method for a temporary increase in a permeability of the blood brain barrier and administering a pharmaceutical substance to the brain, the method comprising: providing a system for transcranial magnetic stimulation in a range of at least 0.2 Hz; placing said system on a scalp; and providing a series of magnetic pulses to the brain via the system. Nanoparticles are not mentioned in this reference.
Numerous papers describe using a magnetic field to facilitate transport of drug-carrying superparamagnetic nanoparticles across the BBB. Nair et al. in US 20110213193, entitled Magnetic nanoparticle to transport API across brain blood barrier, use of magnetic field discuss the use of superparamagnetic nanoparticles to carry drugs through the BBB. Thomsen L B, Linemann T, Pondman K M, Lichota J, Kim K S, Pieters R J, Visser G M and Moos T., “Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells”, ACS Chem Neurosci. 2013 Oct. 16; 4(10), pages 1352-1360 investigated the ability of fluorescent superparamagnetic iron oxide nanoparticles (SPIONs) to pass through human brain microvascular endothelial cells facilitated by an external magnet. The ability of SPIONs to penetrate the barrier was shown to be significantly stronger in the presence of an external magnetic force in an in vitro BBB model. The SPIONs can be coated with ligands or antibodies. Yan F, Wang Y, He S, Ku S, Gu W, Ye L., “Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood-brain barrier”, J Mater Sci Mater Med. 2013 October; 24(10), pages 2371-2379 reported a strategy for brain targeted delivery utilizing the targeting of ligand conjugated nanoparticles to trigger the receptor-mediated transcytosis. In this study, transferrin (TO was employed as a brain targeting ligand to functionalize the fluorescein-loaded magnetic nanoparticles (FMNs). The Tf conjugated FMNs (Tf-FMNs) were characterized by transmission electron microscopy, thermal gravimetric analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Using fluorescein as an optical probe, the potential of Tf-FMNs as brain targeting drug carriers was explored in vivo. It was demonstrated that Tf-FMNs were able to cross the intact BBB, diffuse into brain neurons, and distribute in the cytoplasm, dendrites, axons, and synapses of neurons. In contrast, magnetic nanoparticles without Tf conjugation did not cross the BBB efficiently under the same conditions. Fan C H, Ting C Y, Lin H J, Wang C H, Liu H L, Yen T C, Yeh C K., “SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery”, Biomaterials 2013 May; 34(104), pages 3706-3715. DOX-SPIO-MBs ((doxorubicin; DOX), superparamagnetic iron oxide (SPIO), circulating microbubbles (MBs)) were designed to concurrently open the BBB and perform drug delivery upon FUS exposure, act as dual MRI and ultrasound contrast agent, and allow magnetic targeting (MT) to achieve enhanced drug delivery. The authors reported that DOX-SPIO-MBs were stable and provided significant superparamagnetic/acoustic properties for imaging. BBB-opening and drug delivery were achieved concurrently during the FUS exposure. Kong et al. in “Magnetic targeting of nanoparticles across the intact blood-brain barrier”, Journal of Controlled Release 164 (2012) pages 49-57 “demonstrate in a mouse model that magnetic nanoparticles (MNPs) can cross the normal BBB when subjected to an external magnetic field . . . . Atomic force microscopy demonstrated that MNPs were internalized by endothelial cells, suggesting that trans-cellular trafficking may be a mechanism for the MNP crossing of the BBB.”
Despite these references and other work, there remains a need for improved methods of transporting drugs across the BBB.